Viral infections of the central nervous system (CNS) can result in encephalitis. Viral encephalitis is a risk factor for epilepsy. Epilepsy has an incidence of about 1 to 3% and affects about 2.5 million Americans and more than 50 million individuals worldwide. Seizures result from imbalances between excitatory and inhibitory inputs within the brain. Encephalitis and resulting damage to the CNS can alter these inputs. Infection- initiated seizure disorders are often refractory to many established anti-epileptic drugs. Approximately 30% of individuals with epilepsy are refractory to currently existing anti-seizure medications. Therefore, finding new biological models for epilepsy and potentially new therapeutics are important for the public health. Different virus infections can cause encephalitis that result in seizures. These viruses include herpes viruses such as human herpes virus type-6, influenza viruses, rotaviruses, adenovirus, respiratory syncytial virus and picornaviruses. For example, the human picornavirus, Enterovirus 71, causes encephalitis where patients often present with seizures. A problem that has plagued this field is that a good experimental animal model is not available to investigate how virus encephalitis can lead to epilepsy. Previous animal models have infected rabbits, rats and mice with different viruses. These animals develop acute encephalitis and develop seizures but succumb to the infection. Theiler's murine encephalomyelitis virus (TMEV) is a neurotropic picornavirus. We have developed a new and novel model where infection of C57BL/6 mice with the Daniels virus (DAV) strain of TMEV leads to acute seizures between days 3 and 10 post infection. Mice recover but after a variable latent period mice start to have spontaneous seizures. This is the first infection driven model of temporal lobe epilepsy. We propose to test in Specific Aim 1 the hypothesis that direct virus infection of pyramidal cells of the hippocampus leads to the development of seizures.
In Specific Aim 2 we hypothesize that DAV infection targets a cytokine storm to regions within the CNS that leads to neuronal dysfunction and death. Relevance: Up to 20% of individuals who survive viral encephalitis develop epilepsy. This model is the first infection driven model for epilepsy. Other animal models use electrical stimulation or neurotoxic substances that kill and/or alter neurons in different parts of the brain leading to spontaneous seizures. Our viral model is potentially more relevant particularly for the testing of new therapeutic strategies using an anti- inflammatory approach. As mentioned above about 30% of individuals with epilepsy are refractory to existing anti-seizure medications, and recently the FDA is recommending that warnings be attached to eleven epilepsy drugs disclosing the risk of suicide. Therefore, new approaches are warranted.

Public Health Relevance

Viral infections of the central nervous system result in encephalitis. Viral encephalitis is associated with an increased risk for seizures and the development of epilepsy. We have developed a new and novel mouse model of virus-induced epilepsy. Other animal models for epilepsy use electrical stimulation or neurotoxic substances that kill and/or alter neurons within the CNS leading to spontaneous seizures. Our viral model is potentially more relevant particularly for the testing of new therapeutic strategies that use an anti-inflammatory approach. About 30% of individuals with epilepsy are refractory to existing anti-seizure medications, and recently the FDA is recommending that warnings be attached to eleven epilepsy drugs disclosing the risk of suicide. Therefore, new and novel approaches to this disease are warranted.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065714-03
Application #
8196959
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Fureman, Brandy E
Project Start
2010-01-15
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$320,491
Indirect Cost
$106,116
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Cusick, Matthew F; Libbey, Jane E; Doty, Daniel J et al. (2014) DA virus mutant H101 has altered CNS pathogenesis and causes immunosuppression. J Neuroimmunol 277:118-26
Libbey, Jane E; Fujinami, Robert S (2014) Adaptive immune response to viral infections in the central nervous system. Handb Clin Neurol 123:225-47
Loughran, G; Libbey, J E; Uddowla, S et al. (2013) Theiler's murine encephalomyelitis virus contrasts with encephalomyocarditis and foot-and-mouth disease viruses in its functional utilization of the StopGo non-standard translation mechanism. J Gen Virol 94:348-53
Cusick, Matthew F; Libbey, Jane E; Fujinami, Robert S (2013) Multiple sclerosis: autoimmunity and viruses. Curr Opin Rheumatol 25:496-501
Cusick, Matthew F; Libbey, Jane E; Patel, Dipan C et al. (2013) Infiltrating macrophages are key to the development of seizures following virus infection. J Virol 87:1849-60
Smeal, Roy M; Stewart, Kerry-Ann; Iacob, Eli et al. (2012) The activity within the CA3 excitatory network during Theiler's virus encephalitis is distinct from that observed during chronic epilepsy. J Neurovirol 18:30-44
Cusick, Matthew F; Libbey, Jane E; Fujinami, Robert S (2012) Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol 42:102-11
Libbey, Jane E; Kennett, Nikki J; Wilcox, Karen S et al. (2011) Once initiated, viral encephalitis-induced seizures are consistent no matter the treatment or lack of interleukin-6. J Neurovirol 17:496-9
Libbey, Jane E; Fujinami, Robert S (2011) Neurotropic viral infections leading to epilepsy: focus on Theiler's murine encephalomyelitis virus. Future Virol 6:1339-1350
Libbey, Jane E; Kennett, Nikki J; Wilcox, Karen S et al. (2011) Lack of correlation of central nervous system inflammation and neuropathology with the development of seizures following acute virus infection. J Virol 85:8149-57

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